Effect of Ozonated Olive Oil on Clinical Management of Diabetic Foot Infection, Patient Empowerment, and Foot Self-Care in Individuals with Diabetic Foot Ulcers: A Randomized Controlled Trial

Background: Diabetic foot ulcers are frequently complicated by infection and suboptimal self-management. Objectives: This study evaluated whether topical ozonated olive oil, when added to standard care, improves infection resolution, patient empowerment, and foot self-care. Methods: In this randomized controlled trial, 90 adults with infected diabetic foot ulcers were allocated to receive topical ozonated olive oil plus standard care or standard care alone for 4 weeks. Outcomes were assessed at baseline, immediately after treatment, and 2 months later. The primary outcome was clinical resolution of infection according to the International Working Group on the Diabetic Foot/Infectious Diseases Society of America (IWGDF/IDSA) classification. Patient empowerment and foot self-care were assessed using the IR-DES-28 and Persian DFSQ-UMA, respectively. Repeated measures outcomes were analyzed using linear mixed-effects models. Results: Of the 90 randomized participants, 85 completed follow-up (42 in the intervention group and 43 in the control group). At the post-intervention assessment, clinical resolution occurred in 21/42 (50.0%) participants receiving ozonated olive oil compared with 14/43 (32.6%) participants receiving standard care (RR = 1.54; 95% CI, 0.92 - 2.57; P = 0.102). At the prespecified primary endpoint (two-month follow-up), clinical resolution occurred in 25/42 (59.5%) participants in the intervention group versus 16/43 (37.2%) participants in the control group in the per-protocol analysis (RR, 1.60; 95% CI, 1.01 - 2.54; P = 0.040). In the primary intention-to-treat analysis using multiple imputation, the corresponding rates were 56.8% versus 36.4% (RR, 1.56; 95% CI, 1.01 - 2.41; P = 0.044). However, this result was not robust: a conservative sensitivity analysis using baseline observation carried forward did not reach statistical significance (RR 1.56; 95% CI, 0.98 - 2.49; P = 0.056). The primary efficacy finding is therefore statistically fragile and dependent on missing-data assumptions, and should not be interpreted as evidence of treatment efficacy. Patient empowerment scores improved more in the intervention group, with between-group differences in change of 4.24 points post-intervention (95% CI, 1.63 - 6.86; P = 0.001) and 6.47 points at two months (95% CI, 3.85 - 9.09; P < 0.001). However, these patient-reported outcomes are highly susceptible to performance and expectancy biases due to the unblinded design and should be interpreted as exploratory observations only, not as evidence of treatment effects. Foot self-care improved significantly over time in both groups, but no significant treatment-by-time interaction was observed either immediately after treatment (β = 0.13; P = 0.914) or at two months (β = 0.87; P = 0.484). Six mild local adverse events were reported during follow-up (4 cases of erythema and 2 cases of pruritus); no serious adverse events were reported. The absence of microbiological endpoints precluded evaluation of antimicrobial efficacy. Conclusions: In this randomized controlled trial, adjunctive topical ozonated olive oil was associated with a higher rate of clinical infection resolution at the two-month follow-up in the multiple imputation analysis; however, this finding was not statistically significant under conservative missing-data assumptions and is therefore fragile. The trial was underpowered for the observed effect size, the outcome assessment was susceptible to detection bias due to partial blinding, and no microbiological validation was performed. These preliminary findings do not support clinical implementation and should be considered hypothesis-generating only. Larger, multicenter trials with blinded outcome assessment are needed to confirm these findings.